Implantable medical devices comprising bio-degradable alloys with enhanced degradation rates

ABSTRACT

The invention provides medical devices comprising high-strength alloys which degrade over time in the body of a human or animal, at controlled degradation rates, without generating emboli and which have enhanced degradation due to the presence of a halogen component. In one embodiment the alloy is formed into a bone fixation device such as an anchor, screw, plate, support or rod. In another embodiment the alloy is formed into a tissue fastening device such as staple. In yet another embodiment, the alloy is formed into a dental implant or a stent.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. Application No.14,213,855, filed on Mar. 14, 2014, which claims the benefit of andpriority to U.S. Provisional Application No. 61/785,531, filed on Mar.14, 2013, the contents of each which are hereby incorporated byreference in their entireties for all purposes.

FIELD OF THE INVENTION

The present invention relates to biodegradable materials useful formanufacturing implantable medical devices, specifically biodegradablecompositions comprising iron reactive component containing metal alloysthat can provide high strength when first implanted and are graduallyeroded and replaced with body tissue.

BACKGROUND OF THE INVENTION

Medical devices meant for temporary or semi-permanent implant are oftenmade from stainless steel. Stainless steel is strong, has a great dealof load bearing capability, is reasonably inert in the body, does notdissolve in bodily fluids, and is durable, lasting for many years, ifnot decades. Long lasting medical implants, however, are not alwaysdesirable. Many devices for fixing bones become problematic once thebone has healed, requiring removal by means of subsequent surgery.Similarly, short term devices such as tissue staples have to be removedafter the tissue has healed, which limits their use internally.

Attempts to generate biodegradable materials have traditionally focusedon polymeric compositions. One example is described in U.S. Pat. No.5,932,459, which is directed to a biodegradable amphiphilic polymer.Another example is described in U.S. Pat. No. 6,368,356, which isdirected to biodegradable polymeric hydrogels for use in medicaldevices. Biodegradable materials for use in bone fixation have beendescribed in U.S. Pat. No. 5,425,769, which is directed to CaSO₄ fibrouscollagen mixtures. And U.S. Pat. No. 7,268,205 describes the use ofbiodegradable polyhydroxyalkanoates in making bone fasteners such asscrews. However, none of the biodegradable polymeric materials developedto date have demonstrated sufficient strength to perform suitably whensubstantial loads must be carried by the material, when the material isrequired to plastically deform during implantation, or when any of theother native characteristic of metal are required from the material. Forexample, the polyhydroxyalkanoate compositions described in U.S. Pat.No. 7,268,205 do not have sufficient strength on their own to bearweight and must be augmented by temporary fixation of bone segments. Inaddition, biodegradable polymeric materials tend to lose strength farmore quickly than they degrade, because the portions of the materialunder stress tend to be more reactive, causing preferential dissolutionand breakdown at load-bearing regions.

Metals, particularly steels, are thus preferred for the construction ofmany medical implants. The performance characteristics of steel closelymatch the mechanical requirements of many load bearing medical devices.Although ordinary steel compounds, unlike stainless steel, will degradein biological fluids, they are not suitable for use in biodegradableimplantable medical devices. This is because ordinary steels do notdegrade in a predictable fashion, as one molecule or group of moleculesat a time, which can be easily disposed of by the body. Rather, becauseof their large-grain structures, ordinary steels tend to break down byfirst degrading at grain boundaries, causing fissures and separations inthe medical device, followed by rapid loss of strength and integrity andparticulation. Particulation of the medical device is extremelydangerous because it allows small pieces of the device to leave the areaof implantation and become lodged in other tissues, where they can causeserious injury including organ failure, heart attack and stroke. The useof ordinary steels in implantable medical devices is also complicated bythe fact that ordinary steels typically contain alloying elements thatare toxic when released in the body.

There remains a need in the field to develop additional implantablemedical devices that have desirable characteristics associated withsteel but which are also biodegradable.

SUMMARY OF THE INVENTION

The invention is based, in part, on the discovery that certain metalalloys having an iron reactive component will biodegrade over timewithout forming emboli. The invention is also based, in part, on thediscovery that certain metal alloys having, e.g., an iron reactivecomponent containing alloy which reacts with a bodily fluid when it isin contact with the fluid degrades with a degradation rate that isfaster when implanted in a biological subject than the degradation rateof an alloy having the same composition except that the alloy does notcontain an iron reactive component. Such alloys are useful for makingbiodegradable, implantable medical devices.

In some embodiments, the implantable medical device of the presentinvention comprises a biodegradable alloy, wherein the alloy is ironbased and comprises an iron reactive component, wherein the alloy reactswith a bodily fluid when it is in contact with the fluid and wherein thedegradation rate of the alloy when implanted in a biological subject isfaster than the degradation rate of an alloy having the same compositionas the said alloy except the absence of the iron reactive component.

In some embodiments, the iron reactive component has a boiling pointabove the melting temperature of an alloy having the same compositionexcept the absence of the iron reactive component.

In some embodiments, the iron reactive component is a halogen component.

In some embodiments, the halogen component is provided as a salt. Insome embodiments, the halogen component is selected from sodiumfluoride, sodium chloride, copper chloride, copper fluoride, magnesiumchloride, silver chloride, calcium chloride, calcium fluoride and ironchloride.

In some embodiments, the halogen component is selected from chloride,fluoride, bromide and iodide. In some embodiments, the halogen componentis chloride or fluoride.

In some embodiments, the iron reactive component is in a salt form witha boiling temperature of at least about 1600° C., at least about 1650°C., at least about 1700° C., at least about 1750° C., at least about1800° C., at least about 1850° C., at least about 1900° C., at leastabout 1950° C., or at least about 2000° C.

In some embodiments, the halogen component is halogen. In someembodiments, the halogen is chlorine.

In some embodiments, the iron reactive component is equally dispersedwithin the alloy.

In some embodiments, the iron reactive component is dispersed on thesurface of the alloy.

In some embodiments, the implantable medical device of the presentinvention degrades at a rate of about 1-2 mg per day per square inchwhen placed in purified water.

In some embodiments, the average grain size is about 0.5 microns toabout 5.0 microns. In some embodiments, the average grain size is stableat minimum recrystallization temperature of about 0.55 times theabsolute melting temperature of the alloy.

In some embodiments, the implantable medical device is a bone screw,bone anchor, tissue staple, craniomaxillofacial reconstruction plate,fastener, reconstructive dental implant, or stent.

In some embodiments, the alloy comprises an austenite promotingcomponent and a corrosion resisting component.

In some embodiments, the alloy contains between about 20% to 40%manganese. In some embodiments, the biodegradable alloy comprisesmanganese and niobium. In some embodiments, the alloy contains less thanabout 0.3% niobium. In some embodiments, the alloy contains less thanabout 1% carbon. In some embodiments, the biodegradable alloy comprisesat least about 0.01% to about 0.1% non-metallic element. In someembodiments, the biodegradable alloy comprises at least about 0.01% toabout 0.1% carbon.

In some embodiments, the implantable medical device is coated with atherapeutic agent.

In some embodiments, the implantable medical device is coated with abiodegradable hydrogel.

In some embodiments, the implantable medical device comprises a geometrythat maximizes the surface to mass ratio.

In some embodiments, the implantable medical device comprises a hollowopening or passageway.

In some embodiments, the biodegradable alloy is formed by adding agaseous iron reactive component during the melting process.

In some embodiments, the gaseous iron reactive component has a partialpressure of at least about 0.1 torr, at least about 0.2 torr, at leastabout 0.5 torr, at least about 0.8 torr, at least about 1 torr, at leastabout 2 torr, at least about 5 torr, at least about 10 torr, at leastabout 50 torr or at least about 100 torr.

In some embodiments, the iron reactive component is a halogen component.

In some embodiments, the halogen component is chlorine.

In some embodiments, the gaseous iron reactive component was added tomix with argon gas. In some embodiments, the argon gas has a partialpressure of at least about 10 torr, at least about 20 torr, at leastabout 50 torr, at least about 80 torr, at least about 100 torr, at leastabout 150 torr, at least about 200 torr, at least about 250 torr, atleast about 300 torr, or at least about 500 torr.

The invention and additional embodiments thereof will be set forth ingreater detail in the detailed description that follows.

Accordingly to some embodiments of the present invention, provided is amethod of controlling the degradation rate of an implantable medicaldevice, comprising a step of modulating the concentration of the ironreactive component in the alloy.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “percentage” when used to refer to the amountof an element in an alloy means a weight-based percentage. “Weightedpercentages” of corrosion resisting and austenite promoting components,however, are calculated in a manner such that the weighted percentagesdo not necessarily correspond to the actual weight-based percentages.

The present invention is based, in part, on the discovery that certainmetal alloys having, e.g., an iron reactive component containing alloywhich reacts with a bodily fluid when it is in contact with the fluiddegrades with a degradation rate that is faster when implanted in abiological subject than the degradation rate of an alloy having the samecomposition except that the alloy does not contain an iron reactivecomponent. In some embodiments the alloys of the present invention have,for example, a fine-grain, substantially austenite structure that willbiodegrade over time without forming emboli and that when these alloyscontain an iron reactive component the degradation rate in human oranimal body is enhanced. These austenite alloys exhibit little or nomagnetic susceptibility and low magnetic permeability and can be madenon-toxic and/or non-allergenic by controlling the amounts of variousmetals (e.g., chromium and nickel) incorporated into the alloys. In someembodiments the alloys of the present invention have, for example, asubstantially martensite structure will biodegrade over time withoutforming emboli and that when these alloys contain an iron reactivecomponent the degradation rate in human or animal body is enhanced.These martensite alloys can also be made non-toxic and/or non-allergenicby controlling the amounts of various metals (e.g., chromium and nickel)incorporated into the alloys. The alloys described herein may beincorporated into a variety of implantable medical devices that are usedto heal the body of a subject (e.g., a human or other animal), butbecome unnecessary once the subject is healed. The alloys of the presentinvention can be used, for example, to make biodegradable, implantablemedical devices that require high strength, such as bone fasteners forweight-bearing bones. The alloys can also be used to make biodegradable,implantable medical devices that require ductility, such as surgicalstaples for tissue fixation.

One object of the present invention is to provide medical devices fortemporary implantation in the body of a subject (e.g., a human or animalsubject), wherein the devices are made using a biodegradable alloycomprising an iron reactive component. The biodegradable alloycomprising an iron reactive component is one that is not a stainlesssteel, but instead undergoes reactions involving normal body chemistryto biodegrade or bio-absorb over time and will be removed by normal bodyprocesses. It is another object of the invention to provide implantablemedical devices made using a biodegradable iron reactive componentcontaining alloy that is non-toxic and/or non-allergenic as it isdegrading and being processed by the body. It is yet another object ofthe invention to provide implantable medical devices made using abiodegradable alloy comprising an iron reactive component that haslittle or no magnetic susceptibility and low magnetic permeability anddoes not distort MRI images.

The iron reactive component can be added to the alloy by a variety ofmeans known in the art. In some embodiments, the iron reactive componentis capable of being equally dispersed throughout the alloy. In someembodiments, the iron reactive component is equally dispersed throughoutthe alloy.

In some embodiments, an iron reactive component is added at the time ofmelting of an alloy mixture or at anytime during the melting process.For example, the iron reactive component can be added later in themelting process, prior to the melt being poured into a mold. The ironreactive component can also be dispersed on the surface of the alloy.Such alloys can be generated by a variety of methods known in the art,including for example ion implantation. Ion implantation is well knownand involves the process by which ions of a material are accelerated inan electrical field and impacted onto a solid surface, such as forexample an alloy of the present invention. In some embodiments, the ironreactive component is dispersed on the surface of the alloy. In someembodiments, the iron reactive component is applied to the exteriorsurface of the alloy. In some embodiments, the iron reactive componentis added to the alloy by methods of ion-implanting. See, e.g., Hamm,Robert W.; Hamm, Marianne E., Industrial Accelerators and TheirApplications. World Scientific (2012). An iron reactive component of thepresent invention can include any component which provides for anenhanced alloy degradation rate when the alloy comprising the ironreactive component is exposed to a biological environment (i.e.,implanted in a biological subject), as compared to the same alloy absentthe iron reactive component. In some embodiments, the alloy comprisesmore than one iron reactive component.

According to one aspect of the present invention, small amounts of ironreactive components are useful for controlling the biodegradation rateof suitable alloys. In some embodiments, the concentration of the ironreactive component in the alloy is between about 0.1 ppm to about 1000ppm, between about 0.1 ppm to about 800 ppm, between about 0.1 ppm toabout 600 ppm, between about 0.1 ppm to about 400 ppm, between about 0.1ppm to about 300 ppm, between about 0.1 ppm to about 250 ppm, betweenabout 0.1 ppm to 200 ppm, between about 0.1 ppm to about 150 ppm,between about 0.1 ppm to about 100 ppm, between about 0.1 ppm to about75 ppm, between about 0.1 ppm to about 50 ppm, between about 0.1 ppm toabout 25 ppm or between about 0.1 ppm to about 10 ppm. In someembodiments, the concentration of the iron reactive component in thealloy is between about 1 ppm to 500 ppm, between about 10 ppm to about300 ppm, or between about 50 ppm to about 150 ppm.

In some embodiments, the iron reactive component is stable attemperatures greater than or equal to the melting point of the alloy inthe absence of the iron reactive component. In some embodiments, theiron reactive component is provided as a salt with a boiling temperatureof at least about 1600° C., at least about 1650° C., at least about1700° C., at least about 1750° C., at least about 1800° C., at leastabout 1850° C., at least about 1900° C., at least about 1950° C., or atleast about 2000° C.

In some embodiments, the iron reactive component is provided as a gasduring the fabrication process with a total or partial pressure of atleast about 0.1 torr, at least about 0.2 torr, at least about 0.5 torr,at least about 0.8 torr, at least about 1 torr, at least about 2 torr,at least about 5 torr, at least about 10 torr, at least about 50 torr orat least about 100 torr.

In some embodiments, the iron reactive component is a halogen component.Halogen components of the present invention include halogens and/or thesalt forms such as chloride, fluoride, bromide and iodide. In someembodiments, the halogen component is chlorine. In some embodiments, thehalogen component is chloride or fluoride. In some embodiments thehalogen component is chloride. In some embodiments the halogen componentis fluoride. In some embodiments, the halogen component is stable attemperatures greater than or equal to the melting point of the alloy. Insome embodiments, the alloy containing the iron reactive componentcomprises more than one halogen component.

In some embodiments, the iron reactive component is halogen containingsalt. The halogen component can be provided to the alloy mixture as asalt during the process of generating the alloy. In some embodiments,the halogen containing salt is selected from sodium fluoride, sodiumchloride, copper chloride, copper fluoride, silver chloride, calciumchloride, calcium fluoride and iron chloride. In some embodiments,mixtures of salts can be employed.

In some embodiments, a halogen containing salt is added to the alloymixture at the time of melting or at anytime during the melting process.Any halogen containing salt with a boiling temperature greater than themelting temperature of the alloy can be used with the methods of thepresent invention. In some embodiments, the halogen component isprovided as a salt with a boiling temperature of at least about 1600°C., at least about 1650° C., at least about 1700° C., at least about1750° C., at least about 1800° C., at least about 1850° C., at leastabout 1900° C., at least about 1950° C., or at least about 2000° C. Insome embodiments, the halogen component is stable at temperaturesgreater than or equal to the melting point of the alloy. In someembodiments, more than one halogen component can be employed.

Additionally or alternatively, a gaseous iron reactive component can beused during the process of generating the alloy. In some embodiments,the halogen component is chlorine gas. In some embodiments, the halogencomponent is provided as a gas with a total or partial pressure greaterthan or equal to about 0.1 torr, about 0.2 torr, about 0.5 torr, about0.8 torr, about 1 torr, about 2 torr, about 5 torr, about 10 torr, about50 torr or about 100 torr. In some embodiments, the total or partialpressure of the halogen component is a range of about 0.1 torr to about100 torr, about 0.5 torr to about 50 torr, or about 1 to about 5 torr.

In some embodiments, mixtures of gases can be employed. Without beingbound to any particular theory, it is contemplated that the amount ofthe iron reactive component can be fine tuned by controlling a partialpressure of the iron reactive component with or without additionalgases. In some embodiments, an inert gas such as argon can be providedin a mixture with one or more halogen gases. In some embodiments, theargon gas has a partial pressure of at least about 10 torr, at leastabout 20 torr, at least about 50 torr, at least about 80 torr, at leastabout 100 torr, at least about 150 torr, at least about 200 torr, atleast about 250 torr, at least about 300 torr, or at least about 500torr. As demonstrated in Example 2, approximately 1 torr of chlorine canbe added into 200 torr of argon during the melt process.

In some embodiments, the concentration of the halogen component in thealloy is between about 0.1 ppm to about 500 ppm, between about 0.1 ppmto about 400 ppm, between about 0.1 to about 300 ppm, between about 0.1to about 250 ppm, between about 0.1 to about 200 ppm, between about 0.1ppm to about 150 ppm, between about 0.1 to about 100 ppm, between about0.1 ppm to about 75 ppm, between about 0.1 ppm to about 50 ppm, betweenabout 0.1 to about 25 ppm or between about 0.1 ppm to about 10 ppm. Insome embodiments, the halogen component in the alloy comprises betweenabout 0.1 ppm to about 100 ppm.

Accordingly, in one aspect, the invention provides implantable medicaldevices comprising a biodegradable alloy that dissolves from itsexterior surface. As used herein, the term “alloy” means a mixture ofchemical elements comprising two or more metallic elements.Biodegradable alloys suitable for making implantable medical devices ofthe invention can be, for example, iron alloys (e.g., steels). Incertain embodiments, the iron alloys comprise about 55% to about 65%,about 57.5% to about 67.5%, about 60% to about 70%, about 62.5% to about72.5%, about 65% to about 75%, about 67.5% to about 77.5%, about 70% toabout 80%, about 72.5% to about 82.5%, or about 75% to about 85% iron.The iron alloys further comprise one or more non-iron metallic elements.The one or more non-iron metallic elements can include, for example,transition metals, such as manganese, cobalt, nickel, chromium,molybdenum, tungsten, tantalum, niobium, titanium, zirconium, hafnium,platinum, palladium, iridium, rhenium, osmium, rhodium, etc., ornon-transition metals, such as aluminum. In some embodiments, the ironalloys comprise at least two non-iron metallic elements. The at leasttwo non-iron elements can be present in an amount of at least about 0.5%(e.g., at least about 1.0%, about 1.5%, about 2.0%, about 2.5%, about3.0%, about 4.0%, about 5.0%, or more). In certain embodiments, the ironalloys comprise at least two non-iron metallic elements, wherein each ofsaid at least two non-iron elements is present in an amount of at leastabout 0.5%, and wherein the total amount of said at least two elementsis at least about 15% (e.g., at least about 17.5%, about 20%, about22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about37.5%, or about 40%). The biodegradable alloys can also comprise one ormore non-metallic elements. Suitable non-metallic elements include, forexample, carbon, nitrogen, and silicon. In certain embodiments, the ironalloys comprise at least about 0.01% (e.g., about 0.01% to about 0.10%,about 0.05% to about 0.15%, about 0.10% to about 0.20%, about 0.15% toabout 0.25%, or about 0.20% to about 0.30%) of at least one non-metallicelement.

Biodegradable alloys suitable for use in the implantable medical devicesof the invention are designed to degrade from the outside inward, suchthat they maintain their strength for a greater portion of their lifeand do not particulate or embolize. Without intending to be bound bytheory, it is believed that this is accomplished by providing an alloystructure that either has no appreciable reactive grain boundaries,forcing degradation to take place at the surface molecular layer, or byproviding a very fine grain alloy that acts as a homogeneous, grain freematerial. In certain embodiments, the rate of dissolution from anexterior surface of a suitable biodegradable alloy is substantiallyuniform at each point of the exterior surface. As used herein in thiscontext, “substantially uniform” means that the rate of dissolution froma particular point on an exterior surface is +/−10% of the rate ofdissolution at any other point on the same exterior surface. As personsskilled in the art will appreciate, the type of “exterior surface”contemplated in these embodiments is one that is smooth and continuous(i.e., substantially planar, concave, convex, or the like) and does notinclude sharp edges or similar such discontinuities, as those arelocations where the rate of dissolution is likely to be much higher. A“substantially” planar, concave, or convex surface is a surface that isplanar, concave, convex, or the like and does not contain any bumps,ridges, or grooves that rise above or sink below the surface by morethan 0.5 mm.

Steel alloys have iron as their primary constituent. Depending upon acombination of (i) the elements alloyed with the iron and (ii) thehistorical working of the alloy, steels can have different structuralforms, such as ferrite, austenite, martensite, cementite, pearlite, andbainite. In some instances, steels having the same composition can havedifferent structures. For example, martensite steel is a form of hightensile steel that can be derived from austenite steel. By heatingaustenite steel to between 1750° F. and 1950° F., and then rapidlycooling it to below the martensite transition temperature, the facecentered cubic structure of the austenite steel will reorient into abody centered tetragonal martensite structure, and the martensitestructure will freeze into place. Martensite steel does not haveappreciable grain boundaries, and thus provides no primary dissolutionpath to the interior of the steel. The result is a slow dissolution fromthe outside, without the formation of emboli. Metallurgical examinationof martensitic material will show “pre-austenitic grain boundaries,”places where the austenite grain boundaries once existed, but these arenonreactive traces of the former structure.

Accordingly, in certain embodiments, the biodegradable implantablemedical devices of the invention comprise an alloy containing an ironreactive component (e.g., an iron alloy) having a substantiallymartensite structure. As used herein, the term “substantially martensitestructure” means an alloy having at least 90% martensite structure. Incertain embodiments, the alloy has at least91%^(, 92)%^(, 93)%^(, 94)%^(, 95)%, 96%, 97%, 98%, 99%, 99.5%, 99.8%,99.9% A or more martensite structure.

The martensite alloy can have the composition of any alloy describedherein. For example, in certain embodiments, the martensite alloy isformed from an austenite alloy described herein. In certain embodiments,the martensite alloy comprises carbon, chromium, nickel, molybdenum,cobalt, or a combination thereof. For example, in certain embodiments,the martensite alloy comprises (i) carbon, (ii) chromium and/ormolybdenum, and (iii) nickel and/or cobalt. In certain embodiments, themartensite alloy comprises about 0.01% to about 0.15%, about 0.05% toabout 0.20%, about 0.10% to about 0.25%, about 0.01% to about 0.05%,about 0.05% to about 0.10%, about 0.10% to about 0.15%, or about 0.15%to about 0.20% carbon. In certain embodiments, the martensite alloycomprises about 0.1% to about 6.0%, about 1.0% to about 3.0%, about 2.0%to about 4.0%, about 3.0% to about 5.0%, or about 4.0% to about 6.0%chromium. In certain embodiments, the martensite alloy comprises about0.1% to about 6.0%, about 0.5% to about 2.5%, about 1.0% to about 3.0%,about 1.5% to about 3.5%, about 2.0% to about 4.0%, about 2.5% to about4.5%, about 3.0% to about 5.0%, about 3.5% to about 5.5%, or about 4.0%to about 6.0% molybdenum. In certain embodiments, the martensite alloycomprises about 5.0% to about 9%, about 6.0% to about 10%, about 7.0% toabout 11%, about 8.0% to about 12%, about 9.0% to about 13%, about 10%to about 14%, or about 11% to about 15% nickel. In certain embodiments,the martensite alloy comprises about 5.0% to about 10%, about 7.5% toabout 12.5%, about 10% to about 15%, about 12.5% to about 17.5%, orabout 15% to about 20% cobalt.

In certain embodiments, the martensite alloy contains about 2.0% toabout 6.0%, about 3.0% to about 7.0%, about 3.5% to about 7.5%, about4.0% to about 8.0%, about 4.5% to about 8.5%, or about 5.0% to about9.0% of a corrosion resisting component. In certain embodiments, themartensite alloy contains about 2.5%, about 3.0%, about 3.5%, about4.0%, about 4.5%, about 5.0%, about 5.5%, or about 6.0% of a corrosionresisting component. In certain embodiments, the corrosion resistingcomponent is calculated as a sum of the percentages of corrosionresisting elements (e.g., chromium, molybdenum, tungsten, tantalum,niobium, titanium, zirconium, hafnium, etc.) in the alloy. In otherembodiments, the corrosion resisting component is calculated as aweighted sum of the corrosion resisting elements in the alloy. Incertain embodiments, individual elements in the weighted sum areweighted according to their corrosion resisting efficacy, as compared tochromium. In certain embodiments, the weighted % corrosion resistingcomponent is determined according to the formula: % chromium+%molybdenum+% tungsten+0.5×(% tantalum+% niobium)+2×(% titanium+%zirconium+% hafnium).

In certain embodiments, the martensite alloy contains at least about10%, about 15%, about 18%, about 20%, about 22%, or about 24% of anaustenite promoting component. For example, in certain embodiments, themartensite alloy contains about 10% to about 20%, about 15% to about25%, about 20% to about 30%, about 25% to about 35%, about 30% to about40% of an austenite promoting component. In certain embodiments, themartensite alloy comprises about 22%, about 23%, about 24%, about 25%,about 26%, about 27%, or about 28% of an austenite promoting component.In certain embodiments, the austenite promoting component is calculatedas a sum of the percentages of austenite promoting elements (e.g.,nickel, manganese, cobalt, platinum, palladium, iridium, aluminum,carbon, nitrogen, silicon, etc.) in the alloy. In other embodiments, theaustenite promoting component is calculated as a weighted sum of all theaustenite promoting elements in the alloy. In certain embodiments,individual elements in the weighted sum are weighted according to theiraustenite promoting efficacy, as compared to nickel. In certainembodiments, the weighted % austenite promoting component is calculatedaccording to the formula: % nickel+% platinum+% palladium+%iridium+0.5×(% manganese+% cobalt)+30×(% carbon+% nitrogen).

In certain embodiments, the martensite alloy comprises about 2.0% toabout 4.0%, about 3.0% to about 5.0%, or about 4.0% to about 6.0% of acorrosion resisting component, and about 10% to about 20%, about 15% toabout 25%, about 20% to about 30%, about 25% to about 35%, or about 30%to about 40% of an austenite promoting component. For example, incertain embodiments, the martensite alloy comprises about 3.0% to about5.0% of a corrosion resisting component and about 20% to about 30% of anaustenite promoting component. In certain embodiments, the corrosionresisting and austenite promoting components are calculated as sums ofthe percentages of corrosion resisting and austenite promoting elements,respectively. In other embodiments, the corrosion resisting andaustenite promoting components are calculated as weighted sums of thecorrosion resisting and austenite promoting elements, respectively.

While martensite alloys have the desirable characteristic of lackinggrain boundaries, austenite alloys are particularly useful for medicalimplants because of their low magnetic susceptibility, which can beuseful where the alloy is exposed to a strong magnetic field. It isdesirable for medical implants to have low magnetic susceptibilitybecause they may be used in patients that would have future need ofMagnetic Resonance Imaging (MRI), which utilizes very high magneticfields. A magnetic reactive alloy in a strong magnetic field canexperience heating, causing local tissue stress and damage to tissuesurrounding the implant. Magnetic reactive implants also distort MRIimages, making them unreadable. In addition, austenite alloys canprovide certain mechanical benefits, since they undergo larger plasticdeformations between their elastic limit (yield point) and ultimatefailure, as compared to martensite alloys. For example, whereas amartensite alloy may have a maximum elongation of about 16% to 20%, anaustenite alloy can have a maximum elongation of about 50% to 60%.

Thus, in certain embodiments, the biodegradable implantable medicaldevices of the invention comprise an iron reactive component containingalloy (e.g., an iron alloy) having a substantially austenite structure.As used herein, the term “substantially austenite structure” means atleast 85% austenite structure. In certain embodiments, the alloy has atleast 88%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%,99.8%, 99.9% or more austenite structure. In certain embodiments, theaustenite alloy has substantially no martensite or ferrite structure. Asused herein, the term “substantially no martensite or ferrite structure”means less than 5% (e.g., less than 4%, 3%, 2%, 1%, 0.5%, 0.2%, 0.1%, or0.05%) martensite or ferrite structure. In certain embodiments, theaustenite alloy is characterized by a maximum elongation of about 40% toabout 65% (e.g., about 50% to about 60%).

Austenitic steels have grains with defined boundaries of irregularshape. Since austenite is a face centered cubic structure, the grainstend to be cubic when viewed perpendicular to a major lattice plane. Inaustenite alloys having either very low carbon or very low chromium, itis possible to create a structure with a fine grain size (e.g., about0.5 microns to about 5.0 microns on a side). A cubic austenite grain of2.5 microns has a total surface area of 37.5 square microns and a volumeof 15.625 cubic microns, for a surface to volume ratio of 2.4μ⁻¹ and atotal mass of 0.12 micrograms. Because of the extremely small mass ofthe grain, the grain material reacts as quickly as the grain boundarymaterial when placed in a biological environment, allowing the alloy toshed material from the outside. This, in turn, prevents weakening of thematerial bulk along grain boundaries and grain separation from thematerial bulk of the alloy. As the size of grains increase, however, theratio of surface to volume decreases. Each grain becomes bigger, takinglonger to be absorbed, making it more likely that dissolution will takeplace along grain boundaries, penetrating deeper into the alloy'smaterial bulk and thereby reducing the strength of the alloy.

The rate of biodegradation of iron reactive component containing alloysof the present invention can be further altered by controlling the grainsize and surface to volume ratio of the individual grains. As the grainsize increases, with a commensurate decrease in the surface-to-volumeratio, biodegradation progresses faster toward the center of the device,increasing the total biodegradation rate. However, too large a grainsize can cause separation of grains and adverse effects.

In some embodiments the alloy containing the iron reactive component isan austenite alloy. In certain embodiments, the austenite alloy has anaverage grain size of about 0.5 microns to about 20 microns on eachside. For example, in certain embodiments, the average grain size isabout 0.5 microns to about 5.0 microns, about 2.5 microns to about 7.5microns, about 5.0 microns to about 10 microns, about 7.5 microns toabout 12.5 microns, about 10 microns to about 15 microns, about 12.5microns to about 17.5 microns, or about 15 microns to about 20 micronson each side. In certain embodiments, the average grain size is about0.5 to about 3.0 microns, or about 1.0 micron to about 2.0 microns oneach side. In certain embodiments, the austenite alloy has a structurewherein the surface to volume ratio of individual grains is, on average,greater than 0.1μ⁻¹. For example, in certain embodiments, the surface tovolume ratio of individual grains is, on average, greater than 0.2μ⁻¹,0.3μ⁻¹, 0.4μ⁻¹, 0.5μ⁻¹, 0.6μ⁻¹, 0.7μ⁻¹, 0.8μ⁻¹, 0.9μ⁻¹, 1.0μ⁻¹, 1.5μ⁻¹,2.0μ⁻¹, 2.5μ⁻¹, 3.0μ⁻¹, 3.5μ⁻¹, 4.0μ⁻¹, 4.5μ⁻, 5.0μ⁻¹, 6.0μ⁻¹, 7.0μ⁻¹,8.0μ⁻¹, 9.0μ⁻¹, 10.0μ⁻¹, 11.0μ⁻¹, 12.0μ⁻¹, 13.0μ⁻¹, 14.0μ⁻¹, 15.0μ⁻¹, ormore.

Austenite grain sizes of about 0.5 microns to about 20 microns can beachieved by successive cycles of mechanical working to break down thealloy, followed by thermal recrystallization. The mechanical working ofmaterials, whether done at cold temperatures (i.e. room temperature to200° C.) or at elevated temperatures, causes strain-induced disruptionof the crystal structure, by physically forcing the alloy into a newshape. The most common method of mechanical working of metals is byreducing the thickness of a sheet of metal between two high pressurerolls, causing the exiting material to be substantially thinner (e.g.,20%-60% thinner) than the original thickness. Other methods such asdrawing can also be employed. The process of mechanically working metalsbreaks down larger, contiguous lattice units into different structures.More importantly, it stores substantial strain-induced energy intodistorted lattice members, by straining lattice structure distances tohigher energy arrangements. Subsequent low-temperaturerecrystallization, which takes place at about 0.35 to about 0.55 timesthe absolute melting temperature of the alloy, allows the latticestructure to undergo rearrangements to a lower energy condition, withoutchanges to overall macro dimensions. To accommodate latticerearrangement without gross changes in dimensions, the size ofindividual lattice sub-units, or grains, is reduced, releasingsubstantial strain energy by breaking the lattice into smallersub-units, and producing a finer grain structure. The process ofmechanical working followed by recrystallization can be repeatedserially, producing finer and finer grains.

In certain embodiments, the austenite alloy comprises carbon. Forexample, in certain embodiments, the alloy comprises about 0.01% toabout 0.10%, about 0.02% to about 0.12%, about 0.05% to about 0.15%,about 0.07% to about 0.17%, about 0.10% to about 0.20%, about 0.12% toabout 0.22%, or about 0.15% to about 0.25% carbon. In certainembodiments, the austenite alloy comprises one or more (e.g., two ormore) elements selected from the list consisting of nickel, cobalt,aluminum, and manganese. In certain embodiments, the alloy comprisesabout 2.0% to about 6.0%, about 3.0% to about 7.0%, about 4.0% to about8.0%, or about 5.0% to about 9.0% nickel. In other embodiments, thealloy comprises substantially no nickel. In certain embodiments, thealloy comprises about 10% to about 20%, about 15% to about 20%, about15% to about 25%, about 18% to about 23%, about 20% to about 25%, orabout 20% to about 30% cobalt. In certain embodiments, the alloycomprises less than about 5.0% (e.g., less than about 4.5%, about 4.0%,about 3.5%, about 3.0%, or about 2.5%) manganese. In certainembodiments, the alloy comprises about 0.5% to about 1.5%, about 1.0% toabout 2.0%, or about 1.5% to about 2.5% manganese. In other embodiments,the alloy comprises about 1.0% to about 8.0%, about 6.0% to about 10%,about 8.0% to about 12%, or about 10% to about 14% manganese. In otherembodiments, the alloy comprises about 10% to about 50%, about 15% toabout 45%, about 20% to about 40%, about 25% to about 35%, or about 25%to about 30% manganese. In certain embodiments, the austenite alloycomprises one or more (e.g., two or more) elements selected from thelist consisting of chromium, molybdenum, and tantalum. In certainembodiments, the alloy comprises about 0.5% to about 1.5%, about 1.0% toabout 2.0%, about 1.5% to about 2.5%, or about 2.0% to about 3.0%chromium. In other embodiments, the alloy comprises substantially nochromium. In certain embodiments, the alloy comprises about 0.5% toabout 1.5%, about 1.0% to about 2.0%, about 1.5% to about 2.5%, or about2.0% to about 3.0% molybdenum. In certain embodiments, the alloycomprises about 1.0% to about 3.0%, about 2.0% to about 4.0%, about 3.0%to about 5.0%, or about 4.0% to about 6.0% tantalum. In certainembodiments, the austenite alloy comprises (i) carbon, (ii) at least twoelements selected from the list consisting of nickel, cobalt, aluminum,and manganese, and (iii) at least two elements selected from the listconsisting of chromium, molybdenum, and tantalum.

Aside from the pattern of dissolution, the rate of dissolution and therelease of potentially toxic elements needs to be controlled in alloysused to make implantable medical devices of the invention. Theparticular elements used to make up an alloy help determine the physicaland chemical properties of the resulting alloy. For example, addingsmall amounts of carbon to iron changes the structure of the iron,creating steel that is greatly increased in hardness and strength, whilechanging the plasticity relative to iron. Similarly, stainless steelsare fabricated by adding elements to the iron that decrease corrosion(i.e., corrosion resisting components), such as chromium and molybdenum.A stainless steel that resists corrosion in a biological system cancontain, for example, 18% chromium and 1% molybdenum. Titanium, niobium,tantalum, vanadium, tungsten, zirconium, and hafnium likewise provide aprotective effect that slows down the rate of degradation of steel in abiologic system.

A stainless steel that does not break down in the intended biologicalsystem is typically not suitable for use in a biodegradable implant.Thus, alloys having large quantities of corrosion resisting elements,such as chromium, molybdenum, titanium, and tantalum, usually cannot beused to make biodegradable implantable medical devices of the invention.However, small quantities of such corrosion resisting elements areuseful for controlling the biodegradation rate of suitable alloys.Accordingly, in certain embodiments, an alloy useful for making abiodegradable implantable medical device of the invention (e.g., anaustenite alloy) contains at least about 0.5%, about 1.0%, about 1.5%,about 2.0%, about 2.5%, about 3.0%, or about 3.5%, but less than about15%, about 12%, about 11%, about 10%, about 9.0%, about 8.0% or about7.0% of a corrosion resisting component. For example, in certainembodiments, the alloy contains about 1.0% to about 7.0%, about 2.0% toabout 8.0%, or about 3.0% to about 9.0% of a corrosion resistingcomponent. In certain embodiments, the alloy (e.g., austenite alloy)contains about 3.0%, about 3.5%, about 4.0%, about 4.5%, about 5.0%,about 5.5%, about 6.0%, about 6.5%, or about 7.0% of a corrosionresisting component. In certain embodiments, the corrosion resistingcomponent is calculated as a sum of the percentages of corrosionresisting elements (e.g., chromium, molybdenum, tungsten, tantalum,niobium, titanium, zirconium, hafnium, etc.) in the alloy. In otherembodiments, the corrosion resisting component is a weighted sum of allthe corrosion resisting elements in the alloy. For example, in certainembodiments, individual elements in the weighted sum are weightedaccording to their corrosion resisting efficacy, as compared tochromium. In certain embodiments, the weighted % corrosion resistingcomponent is determined according to the formula: % chromium+%molybdenum+% tungsten+0.5×(% tantalum+% niobium)+2×(% titanium+%zirconium+% hafnium).

Corrosion resisting elements, such as chromium and molybdenum, areferrite promoting and tend to cause steel to form a ferritic structure.To overcome such ferrite promotion and achieve an austenite structure,austenite promoting elements can be added to the alloy. Austenitepromoting elements include, for example, nickel, manganese, cobalt,platinum, palladium, iridium, aluminum, carbon, nitrogen, and silicon.Accordingly, in certain embodiments, an alloy (e.g., an austenite alloy)useful for making an implantable medical device of the inventioncontains an austenite promoting component. In certain embodiments, thealloy contains about 10% to about 20%, about 15% to about 25%, about 20%to about 30%, about 25% to about 35%, or about 30% to about 40% of anaustenite promoting component. In certain embodiments, the alloycontains at least about 10%, about 12%, about 14%, about 16%, about 18%,about 20%, about 22%, about 24%, about 26%, about 28%, or about 30% ofan austenite promoting component. In certain embodiments, the austenitepromoting component is calculated as a sum of the percentages ofaustenite promoting elements (e.g., nickel, cobalt, manganese, platinum,palladium, iridium, aluminum, carbon, nitrogen, silicon, etc.) in thealloy. In other embodiments, the austenite promoting component is aweighted sum of the austenite promoting elements in the alloy. Incertain embodiments, individual elements in the weighted sum areweighted according to their austenite promoting efficacy, as compared tonickel. In certain embodiments, the weighted % austenite promotingcomponent is calculated according to the formula: % nickel+% platinum+%palladium+% iridium+0.5×(% manganese+% cobalt)+30×(% carbon+% nitrogen).In certain embodiments, the alloy contains a weighted % austenitepromoting component of about 15% to about 25% (e.g., about 16%, about17%, about 18%, about 19%, about 20%, about 21%, about 22%, about 23%,about 24%, or about 25%). In certain embodiments, the alloy contains anunweighted % austenite promoting component of about 25% to about 35%(e.g., about 28%, about 29%, about 30%, about 31%, about 32%, about 33%,about 34%, or about 35%).

In certain embodiments, an iron reactive component containing alloy(e.g., an austenite alloy containing an iron reactive component) usefulfor making an implantable medical device of the invention contains lessthan about 5.0% (e.g., about 0.1% to about 2.5%, about 0.5% to about3.0%, about 1.0% to about 3.5%, about 1.5% to about 4.0%, or about 2.0%to about 4.5%) of platinum, iridium, and osmium, either individually orin total. In certain embodiments, the alloy contains substantially noplatinum, palladium, or iridium. As used herein, “substantially no”platinum, palladium, or iridium means that the alloy contains less than0.1% of platinum, palladium, or iridium. In certain embodiments, thealloy contains substantially no platinum, palladium, and iridium. Incertain embodiments, the alloys contain less than about 0.05%, or about0.01% of each of platinum, palladium, or iridium. In certainembodiments, the alloys contain less than about 0.05%, or less thanabout 0.01%, of each of platinum, palladium, and iridium. In otherembodiments, the total amount of platinum, iridium, and osmium in thealloy is about 5.0% or greater, and the alloy further comprises at leastone additional metal element other than iron, manganese, platinum,iridium, and osmium (e.g., at least about 0.5% or more of said at leastone additional metal element). In certain embodiments, the at least oneaddition metal element is a corrosion resisting element (e.g., chromium,molybdenum, tungsten, titanium, tantalum, niobium, zirconium, orhafnium) or a austenite promoting element selected from the groupconsisting of nickel, cobalt, and aluminum.

Biodegradable iron reactive component containing alloys implanted in ahuman or animal body need to be relatively non-toxic because all of theelements in the alloys will eventually be dissolved into body fluids.Nickel is often used to stabilize an austenitic crystal structure.However, many people have nickel allergies and cannot tolerate nickelions in their systems. Having nickel as part of a biodegradable alloyguarantees that all of the nickel in the alloy will eventually beabsorbed by the host's body, which can cause complications in a nickelsensitive individual. Likewise, chromium, cobalt, and vanadium have sometoxicity in the human body, and should be minimized in a biodegradablealloy. Accordingly, in certain embodiments, an alloy useful for making abiodegradable implantable medical device of the invention (e.g., anaustenite alloy) contains less than about 9.0%, about 8.0%, about 7.0%,about 6.0%, about 5.0%, about 4.0%, about 3.0%, about 2.5%, about 2.0%,about 1.5%, about 1.0%, or about 0.5% of each of nickel, vanadium,chromium, and cobalt. In certain embodiments, the alloy containssubstantially no nickel. As used here, the phrase “substantially nonickel” means that the alloy contains 0.1% or less nickel. In certainembodiments, the alloy contains less than about 0.05%, less than about0.02%, or less than about 0.01% nickel. In certain embodiments, thealloy contains substantially no vanadium. As used here, the phrase“substantially no vanadium” means that the alloy contains 0.1% or lessvanadium. In certain embodiments, the alloy contains less than about0.05%, less than about 0.02%, or less than about 0.01% vanadium. Incertain embodiments, the alloy contains less than about 4.0% chromium(e.g., less than about 3.0%, about 2.0%, or about 1.5%). In certainembodiments, the alloy contains substantially no chromium. As used here,the phrase “substantially no” chromium means that the alloy contains0.1% or less chromium. In certain embodiments, the alloy contains lessthan about 0.05%, less than about 0.02%, or less than about 0.01%chromium. In certain embodiments, the alloy contains less than about6.0% (e.g., less than about 5.0%, about 4.0%, about 3.0%, about 2.0%, orabout 1.0%) cobalt.

To remove or minimize toxic elements from the alloys used to created thebiodegradable implantable medical devices of the invention, the toxicelements can be replaced with non-toxic counterparts. For example, sincenickel is used as an austenite promoting element, it can be replacedwith other austenite promoting elements, such as manganese, cobalt,platinum, palladium, iridium, aluminum, carbon, nitrogen, and silicon.Similarly, since chromium is used as a corrosion resisting element, itcan be replaced with other corrosion resisting elements, such asmolybdenum, tungsten, titanium, tantalum, niobium, zirconium, andhafnium. However, not all alloy substitutions are equivalent. For acorrosion resisting effect, molybdenum is as effective as chromium,while niobium and tantalum are only half as effective as chromium, andtitanium is twice as effective as chromium. For austenite promotingeffect, manganese and cobalt are only half as effective as nickel, whilecarbon is 30 times more effective than nickel, and nitrogen is 25-30times more effective than nickel. Accordingly, in certain embodiments, abiodegradable alloy is rendered non-allergenic or less allergenic byreplacing one part of nickel with two parts manganese, one part ofmanganese and one part of cobalt, or two parts of cobalt. In otherembodiments, a biodegradable alloy is rendered non-toxic or less toxicby replacing one part of chromium with one part of molybdenum, half apart of titanium, or two parts of tantalum or niobium. In someembodiments, the total percentage of manganese is from about 10% toabout 50%, about 15% to about 45%, or about 20% to about 40%, about 25%to about 35%, or about 25% to about 30%, or about 30%. In certainembodiments, the total percentage of nickel, cobalt and manganese isfrom about 10% to about 50%, about 15% to about 45%, or about 20% toabout 40%, about 25% to about 35%, or about 25% to about 30%, whereinthe percentage of nickel is less than about 9.0%, about 8.0%, about7.0%, about 6.0%, about 5.0%, about 4.0%, or about 3.0%. In otherembodiments, the total percentage of chromium and molybdenum is fromabout 1.0% to about 7.0%, about 2.0% to about 8.0%, about 3.0% to about9.0%, or about 4.0% to about 10%, wherein the amount of chromium is lessthan about 2.0%, about 1.5%, about 1.0%, or about 0.5%.

Additional elements that can be included in alloys useful for makingbiodegradable, implantable medical devices of the invention includerhodium, rhenium, and osmium. In certain embodiments, the amount ofrhodium, rhenium, or osmium in the alloy is less than about 5.0% (e.g.,about 0.1% to about 2.5%, about 0.5% to about 3.0%, about 1.0% to about3.5%, about 1.5% to about 4.0%, or about 2.0% to about 4.5%). In certainembodiments, there is substantially no rhodium, rhenium, or osmium inthe alloy. As used herein, “substantially no” rhodium, rhenium, orosmium means that the alloy contains less than about 0.1% of rhodium,rhenium, or osmium. In certain embodiments, there is substantially norhodium, rhenium, and osmium in the alloy. In certain embodiments, thealloy contains less than about 0.05%, or less than about 0.01%, ofrhodium, rhenium, or osmium. In certain embodiments, the alloy containsless than about 0.05%, or less than about 0.01%, of each of rhodium,rhenium, and osmium.

In certain embodiments, when one or more elements selected from thegroup consisting of platinum, palladium, iridium, rhodium, rhenium, andosmium is present in an alloy useful for making biodegradable,implantable medical devices of the invention, the amount of manganese inthe alloy is less than about 5.0% (e.g., less than about 4.5%, about4.0%, about 3.5%, about 3.0%, or about 2.5%). In other embodiments, whenone or more elements selected from the group consisting of platinum,palladium, iridium, rhenium, rubidium, and osmium is present in thealloy and the amount of manganese in the alloy is about 5.0% or greater(e.g., about 5.0% to about 30%), then the alloy further comprises atleast one additional metal element. In certain embodiments, the at leastone addition metal element is a corrosion resisting element (e.g.,chromium, molybdenum, tungsten, titanium, tantalum, niobium, zirconium,or hafnium) or a austenite promoting element selected from the groupconsisting of nickel, cobalt, and aluminum.

In certain embodiments, alloys useful for making biodegradable,implantable medical devices of the invention contain substantially norubidium or phosphorus. As used herein, “substantially no” rubidium orphosphorus means less than 0.1% of rubidium of phosphorus. In certainembodiments, the alloys contain substantially none rubidium andphosphorus. In certain embodiments, the alloys contain less than about0.05%, or less than about 0.01%, of rubidium or phosphorus. In certainembodiments, the alloys contain less than about 0.05%, or less thanabout 0.01%, of each of rubidium and phosphorus.

In certain embodiments, the present invention provides biodegradableimplantable medical devices comprising a range of biodegradable alloys(e.g., austenitic alloys) that are acceptably non-allergenic, non-toxic,has little or no magnetic susceptibility and low magnetic permeability,and provide a useful range of degradation rates. The following areexemplary boundaries defining alloys useful in the biodegradableimplantable medical devices of the present invention:

-   -   an iron reactive component;    -   substantially no nickel;    -   substantially no vanadium;    -   less than about 6.0% chromium;    -   less than about 10% cobalt;    -   a corrosion resisting component of less than about 10% (e.g.,        about 0.5% to about 10%); and    -   an austenite promoting component of at least about 10% (e.g.,        about 10% to about 40%).

In certain embodiments, the present invention provides biodegradableimplantable medical devices comprising a range of biodegradable alloys(e.g., austenitic alloys) that are acceptably non-allergenic, non-toxic,has little or no magnetic susceptibility and low magnetic permeability,and provide a useful range of degradation rates. The following areexemplary boundaries defining alloys useful in the biodegradableimplantable medical devices of the present invention:

-   -   an iron reactive component;    -   28%-30% manganese;    -   0.07%-0.09% carbon;    -   0.18%-0.22% Niobium;    -   a corrosion resisting component of less than about 10% (e.g.,        about 0.5% to about 10%); and    -   an austenite promoting component of at least about 10% (e.g.,        about 10% to about 40%).

In certain embodiments, the present invention provides biodegradableimplantable medical devices comprising a range of biodegradable alloys(e.g., austenitic alloys) that are acceptably non-allergenic, non-toxic,has little or no magnetic susceptibility and low magnetic permeability,and provide a useful range of degradation rates. The following areexemplary boundaries defining alloys useful in the biodegradableimplantable medical devices of the present invention:

-   -   an iron reactive component;    -   28%-30% manganese;    -   0.18%-0.22% niobium;    -   <0.01% carbon;    -   a corrosion resisting component of less than about 10% (e.g.,        about 0.5% to about 10%); and    -   an austenite promoting component of at least about 10% (e.g.,        about 10% to about 40%).

In certain embodiments, the present invention provides biodegradableimplantable medical devices comprising a range of biodegradable alloys(e.g., austenitic alloys) that are acceptably non-allergenic, non-toxic,has little or no magnetic susceptibility and low magnetic permeability,and provide a useful range of degradation rates. The following areexemplary boundaries defining alloys useful in the biodegradableimplantable medical devices of the present invention:

-   -   an iron reactive component;    -   28-30% manganese;    -   0.07-0.09% carbon;    -   a corrosion resisting component of less than about 10% (e.g.,        about 0.5% to about 10%); and    -   an austenite promoting component of at least about 10% (e.g.,        about 10% to about 40%).

In certain embodiments, the alloys contain about 55% to about 80% iron.For example, in certain embodiments, the alloys contain about 55% toabout 65%, about 60% to about 70%, about 65% to about 75%, about 70% toabout 80% iron. In certain embodiments, the amount of chromium is lessthan about 4.0% and the amount of cobalt is less than about 6.0%. Incertain embodiments, the amount of chromium is less than about 2.0% andthe amount of cobalt is less than about 4.0%. In certain embodiments,the corrosion resisting component is less than about 8.0% (e.g., about0.5% to about 8.0%) and the austenite promoting component is greaterthan about 12%. In certain embodiments, the corrosion resistingcomponent is less than less than about 7.0% (e.g., about 0.5% to about7.0%) and the austenite promoting component is greater than about 14%.In certain embodiments, the corrosion resisting component is less thanabout 6.0% (e.g., about 0.5% to about 6.0%) and the austenite promotingcomponent is greater than about 16%. In certain embodiments, thecorrosion resisting and austenite promoting components are calculated assums of the percentages of corrosion resisting and austenite promotingelements, respectively. In other embodiments, the corrosion resistingand austenite promoting components are calculated as weighted sums ofthe corrosion resisting and austenite promoting elements, respectively.In certain embodiments, the weighted % corrosion resisting component isdetermined according to the formula: % chromium+% molybdenum+%tungsten+0.5×(% tantalum+% niobium)+2×(% titanium+% zirconium+%hafnium). In certain embodiments, the weighted % austenite promotingcomponent is calculated according to the formula: % nickel+% platinum+%palladium+% iridium+0.5×(% manganese+% cobalt)+30×(% carbon+% nitrogen).In certain embodiments, the alloys contain less than about 5.0%manganese (e.g., less than about 4.5%, about 4.0%, about 3.5%, about3.0%, or about 2.5%). In certain embodiments, the alloys contain one ormore elements selected from the group consisting of platinum, palladium,iridium, rhodium, rhenium, and osmium. In certain embodiments, thealloys contain about 0.5% to about 5.0% of one or more elements selectedfrom the group consisting of platinum, palladium, iridium, rhodium,rhenium, and osmium. In certain embodiments, the alloys containsubstantially none of the elements selected from the group consisting ofplatinum, palladium, iridium, rhodium, rhenium, and osmium. In certainembodiments, the alloys contain substantially none of the elementsselected from the group consisting of rubidium and phosphorus.

The biodegradation rate of the implantable medical devices of thepresent invention is enhanced by the presence of the iron reactivecomponent in the alloy. As such, the incorporation of a halogencomponent into the alloy of an implantable medical device provides anovel method for enhancing biodegradation. In some embodiments, thealloy containing the iron reactive component reacts with a bodily fluidwhen it is in contact with the fluid. In some embodiments, thedegradation rate of the alloy comprising the iron reactive componentwhen implanted in a biological subject is faster than the degradationrate of an alloy having the same composition as except the iron reactivecomponent is absent. In some embodiments, the implantable medicaldevices of the present invention have a degradation rate of about 1-100mg per day per square inch, about 1-50 mg per day per square inch, about1-20 mg per day per square inch, about 1-10 mg per day per square inch,about 1-5 mg per day per square inch, or about 1-1.5 mg per day persquare inch when placed in pure water or a solution that does notcontain a halogen component. In some embodiments, the implantablemedical devices of the present invention have a degradation rate ofabout 1-2 mg per day per square inch when placed in pure water or asolution that does not contain a halogen component. In some embodiments,the implantable medical devices of the present invention have adegradation rate of about 1.2 mg per day per square inch and 1.4 mg perday per square inch. The degradation rate of biodegradable materials ina human or animal body is a function of the environment surrounding theimplantable medical device.

In embodiments where the iron reactive component is a halogen component,the degradation of the biodegradable material in an environmentcontaining a halogen is faster than in an environment with lowerconcentrations of halogen or lacking a halogen (i.e., a halogen poor orabsent environment). Halogens in the environment speed the degradationof the implantable medical device, but do not become part of thedegradation products, which include oxides, phosphates and carbonates.The biodegradation rate is further enhanced by the presence of a halogenin the solution in which the implantable medical device is immersed. Insome embodiments, the biodegradation rate is enhanced by the presence ofthe halogen component in the alloy. In some embodiments, thebiodegradation rate is enhanced by the presence of the halogen componenton the exterior of the implantable medical device.

The degradation of an entire implant is an additionally a function ofthe mass of the implant as compared to its surface area. Implants comein many different sizes and shapes. A typical coronary stent, forexample, weighs 0.0186 grams and has a surface area of 0.1584square-inches. At a degradation rate of 1 mg/square-inch/day, a coronarystent would loose 50% of its mass in 30 days. In comparison, a 12 mmlong cannulated bone screw weighs 0.5235 g and has a surface area of0.6565 square-inches. At the same degradation rate of 1mg/square-inch/day, the cannulated screw will loose half of its mass in363 days. Thus, as persons skilled in the art will readily appreciate,it is desirable to have biodegradable alloys that have a range ofdegradation rates to accommodate the variety of implants used in thebody of a subject.

In addition, the biodegradation rate of the implantable medical devicesof the present invention are significantly influenced by the transportcharacteristics of the surrounding tissue. For example, thebiodegradation rate of an implant placed into bone, where transport tothe rest of the body is limited by the lack of fluid flow, would beslower than a vascular stent device that is exposed to flowing blood.Similarly, a biodegradable device embedded in tissue would have slowerdegradation rate than a device exposed to flowing blood, albeit a fasterdegradation rate than if the device was embedded in bone. Moreover,different ends of a medical device could experience different rates ofdegradation if, for example, one end is located in bone and the otherend is located in tissue or blood. Modulation of biodegradation ratesbased on the location of the device and ultimate device requirements isthus desirable.

In order to control the dissolution rate of a medical device independentof the geometric shape changes that occur as the device degrades,several techniques have been developed. The first method to alter thedissolution profile of a metallic device is to alter the geometry of thedevice such that large changes in surface area are neutralized. Forexample, the surface to mass ratio can be increased or maximized. Asubstantially cylindrical device, which would lose surface area linearlywith the loss of diameter as the device degrades, could have aconcentric hole drilled through the center of the device. The resultingcavity would cause a compensating increase in surface area as alloy wasdissolved from the luminal surface of the device. As a result, thechange in surface area as the device degrades over time—and thus thechange in rate of degradation—would be minimized or eliminated. Asimilar strategy of creating a luminal space (e.g., a luminal space thathas a shape similar to the outer surface of the device) could beimplemented with essentially any type of medical device.

Because biodegradation rates are partially a function of exposure tobodily fluid flow, biodegradation rates can be modified by coating(e.g., all or part of) the biodegradable implantable medical device witha substance that protects the alloy surface. For example, biodegradablehydrogels, such as disclosed in U.S. Pat. No. 6,368,356, could be usedto retard exposure of any parts of a device exposed to mobile bodilyfluids, thereby retard dissolution and transport of metal ions away fromthe device. Alternatively, medical devices can be constructed with twoor more different alloys described herein, wherein parts of the devicethat are exposed to mobile bodily fluids are made from more corrosionresistant alloys (i.e., alloys comprising higher amounts of a corrosionresisting component), while parts of the device imbedded in bone ortissue are made from less corrosion resistant alloys. In certainembodiments, the different parts of the device can be made entirely fromdifferent alloys. In other embodiments, parts of the device exposed tomobile bodily fluids can have a thin layer or coating of an alloy thatis more corrosion resistant than the alloy used to make the bulk of thedevice.

It is frequently desirable to incorporate bioactive agents (e.g., drugs)on implantable medical devices. For example, U.S. Pat. No. 6,649,631claims a drug for the promotion of bone growth which can be used withorthopedic implants. Bioactive agents may be incorporated directly onthe surface of an implantable medical device of the invention. Forexample, the agents can be mixed with a polymeric coating, such as ahydrogel of U.S. Pat. No. 6,368,356, and the polymeric coating can beapplied to the surface of the device. Alternatively, the bioactiveagents can be loaded into cavities or pores in the medical devices whichact as depots such that the agents are slowly released over time. Thepores can be on the surface of the medical devices, allowing forrelatively quick release of the drugs, or part of the gross structure ofthe alloy used to make the medical device, such that bioactive agentsare released gradually during most or all of the useful life of thedevice. The bioactive agents can be, e.g., peptides, nucleic acids,hormones, chemical drugs, or other biological agents, useful forenhancing the healing process.

As persons skilled in the art will readily recognize, there are a widearray of implantable medical devices that can be made using the alloysdisclosed herein. In certain embodiments, the implantable medical deviceis a high tensile bone anchor (e.g., for the repair of separated bonesegments). In other embodiments, the implantable medical device is ahigh tensile bone screw (e.g., for fastening fractured bone segments).In other embodiments, the implantable medical device is a high strengthbone immobilization device (e.g., for large bones). In otherembodiments, the implantable medical device is a staple for fasteningtissue. In other embodiments, the implantable medical device is acraniomaxillofacial reconstruction plate or fastener. In otherembodiments, the implantable medical device is a dental implant (e.g., areconstructive dental implant). In still other embodiments, theimplantable medical device is a stent (e.g., for maintaining the lumenof an opening in an organ of an animal body).

Powdered metal technologies are well known to the medical devicecommunity. Bone fasteners having complex shapes are fabricated by highpressure molding of a powdered metal in a carrier, followed by hightemperature sintering to bind the metal particles together and removethe residual carrier. Powdered metal devices are typically fabricatedfrom nonreactive metals such as 316LS stainless steel. The porosity ofthe finished device is partially a function of the metal particle sizeused to fabricate the part. Because the metal particles are much largerand structurally independent of the grains in the metal's crystalstructure, metal particles (and devices made from such particles) can bemade from alloys of any grain size. Thus, biodegradable implantablemedical devices of the invention can be fabricated from powders madefrom any of the alloys described herein. The porosity resulting from thepowdered-metal manufacturing technique, can be exploited, for example,by filling the pores of the medical devices with biodegradable polymers.The polymers can be used to retard the biodegradation rates of all orpart of the implanted device, and/or mixed with bioactive agents (e.g.,drugs) that enhance the healing of the tissue surrounding the device. Ifthe porosity of the powdered metal device is filled with a drug, thedrug will be delivered as it becomes exposed by the degradation of thedevice, thereby providing drug to the tissue site as long as the deviceremains present and biodegrading.

In certain embodiments, the implantable medical device is designed forimplantation into a human. In other embodiments, the implantable medicaldevice is designed for implantation into a pet (e.g., a dog, a cat). Inother embodiments, the implantable medical device is designed forimplantation into a farm animal (e.g., a cow, a horse, a sheep, a pig,etc.). In still other embodiments, the implantable medical device isdesigned for implantation into a zoo animal.

In another aspect, the invention provides a container containing animplantable medical device of the invention. In certain embodiments, thecontainer is a packaging container, such as a box (e.g., a box forstoring, selling, or shipping the device). In certain embodiments, thecontainer further comprises an instruction (e.g., for using theimplantable medical device for a medical procedure).

All publications, patent applications, and issued patents cited in thisspecification are herein incorporated by reference as if each individualpublication, patent application, or issued patent were specifically andindividually indicated to be incorporated by reference in its entirety.

The following examples are intended to illustrate, but not to limit, theinvention in any manner, shape, or form, either explicitly orimplicitly. While the specific alloys described exemplify alloys thatcould be used in implantable medical devices of the invention, personsskilled in the art will be able to readily identify other suitablealloys in light of the present specification. Although the foregoinginvention has been described in some detail by way of illustration andexample for purposes of clarity of understanding, it will be readilyapparent to one of ordinary skill in the art in light of the teachingsof this invention that certain changes and modifications may be madethereto without departing from the spirit or scope of the appendedclaims. The following examples are provided by way of illustration onlyand not by way of limitation. Those of skill in the art will readilyrecognize a variety of non-critical parameters that could be changed ormodified to yield essentially similar results.

EXAMPLES Example 1

Background: Biodegradable metal systems have been developed for use incardiovascular, orthopedic, surgical and other applications. Theadvantage of biodegradable metals are that they have high strength andare dissolved by the body and excreted over time until they arecompletely eliminated from the body. These materials are extremelyuseful where an implant is needed for a short period of time, such asfor bone fixation or artery repair, and can have negative impacts afterhealing has take place at the implant site. Stents can cause a stenoticlesion if left in place long after they no longer serve a function andbone fixation devices can cause long term discomfort and are frequentlyremoved after they are no longer required. An example of a biodegradablemetal system is U.S. Pat. No. 8,246,762 which discloses biodegradablemetals for implant that degrade from the surface and consequently do notlose bulk properties of the non-degraded portion of the implant.

The degradation performance of biodegradable materials in a human oranimal body is a function of the environment surrounding the implant.The degradation of the biodegradable material in an environmentcontaining sodium or potassium chloride is faster than in a sodium orpotassium chloride poor environment. Chloride in the environment speedsthe degradation but does not become part of the degradation products,which are normally oxides, phosphates and carbonates. Degradation inareas directly exposed to a flow of body fluid, such as blood, bile,bone marrow or lymph, is faster than material imbedded in tissue orbone, where the flow of fluids required for the degradation reactionsare transported across cellular membranes to the implant. As more fluidand chloride are transported to the site of the implant, thebiodegradation becomes faster and degraded material can be transportedaway from the site more quickly.

One such material is an iron alloy that contains 28% Manganese, 0.2%niobium, 0.08% carbon and the balance iron. When placed in a solution ofsaline 0.9% sodium chloride in water (normal saline), the materialdegrades at a rate of 1.2 mg per day per square inch of surface. Asample of the material 0.69 inches long by 0.39 inches wide by 0.025inches thick was placed in purified water for 123 days. The sample lost0.7 mg per day per square inch of surface, approximately half of thesaline degradation rate. When implanted in the body and surrounded bytissue or bone, the degradation of the material is dependent on theamount and content of the bodily fluid transported to and away from theimplant site and degradation is slowed. However, if the chloride contentat the implant surface can be increased, the degradation rate can beincreased.

Disclosure: It has been found that the degradation profile of iron basedmetals can be altered by including materials that are reactive with ironbased alloys into the alloy at the time it is made or added to thesurface of the alloy after it is final formed. Iron based alloys reactwith chloride ions in solution as is demonstrated by increaseddegradation of alloys in saline solution as compared with purifiedwater. Some body fluids can become chloride deficient. Adding chlorideto the alloy causes the chloride located at the surface or the alloy toreact with the alloy when it comes in contact with a fluid regardless ofthe fluid composition. In addition, the chloride at the surface of thealloy upsets the osmotic equilibrium at the site causing an increase influid migrating to the site. It is not just chloride ion that increasesthe degradation of iron based compounds, the other halogens such asfluoride and iodide and bromide have the same effect.

Adding halogens to an alloy can be accomplished by adding small amountsof halogen compounds, which have boiling points above the meltingtemperature of the alloy mix at the time it is melted. In someembodiments, the halogen compound is stable on heating to alloyingtemperatures and capable of being dispersed in the alloy withoutappreciable segregating at the grain boundaries. Examples of usefulcompounds are sodium fluoride, sodium chloride, copper chloride, silverchloride, calcium chloride and iron chloride.

Four ingots of approximately 28% manganese, 0.2% niobium, 0.08% carbonand the balance iron were fabricated with the addition of 100 ppm ofchloride from one of sodium chloride, calcium chloride, sodium fluorideand copper chloride salts. The fabricated ingots were hot worked andcold rolled to approximately 0.025 inches thick. Samples of each ingotwere placed in purified water with no chloride or fluoride present andexperienced degradation rates of between 1.2 mg per day per square inchand 1.4 mg per day per square inch of sample—essentially the expecteddegradation rate in saline of the base material without the addition ofa chloride source.

Alternatively, a halogen may be applied to the exterior surface of analloy or an implant fabricated from an alloy by ion-implanting thesurface with a halogen such as chlorine or fluorine. Ion-implanting is awell understood process that is practiced on large scale to modify thechemical structure and properties of semiconductors and metals. Byion-implanting a halogen onto the surface structure of a metal, thereaction at the surface can be moderated and because the halogen is notconsumed by the degradation products, it is available to continue thedegradation process as long as it is not transported away from the site.

Samples of an alloy consisting of 28% manganese, 0.2% niobium, 0.08%carbon and the balance iron was electropolished, fastened to a siliconwafer and the surface successfully implanted with 10¹⁵ molecules ofchlorine at an accelerating voltage of 100 key. The experiment wasrepeated with fluorine. Each sample had one side implanted with either achlorine and fluorine and the reverse side was left as native alloy. Thesamples were placed in distilled water and examined twice daily. Thehalogen implanted surface began to degrade in one day while the nativesurface took several days.

Example 2

Fabrication of a biodegradable material with enhanced degradation ratesmay be facilitated through the use of a partial pressure of a gaseousreactive component during the fabrication process. For example, aprocedure for the initial fabrication of a metal alloy is to place someor all of the desired components of the alloy into the crucible of avacuum induction furnace, evacuate the furnace and melt the componentsunder vacuum and/or with a partial pressure of argon. Without beingbound to any particular theory, it is recognized in the presentinvention a partial pressure of argon can be used to minimizeevaporative loss of the desired components and to prevent metal plasmaforming in the furnace chamber which would cause damage to the furnace.After the alloy is fully melted and mixed, it is poured into a mold andcooled.

In some embodiments, it is desirable to add the some components of themetal alloy at a later stage of the melting process. To add componentsto the melt they are contained separately in an addition chamber andreleased into the crucible at the appropriate time. The reactivecomponents of this invention in some embodiments can be added later inthe melting process, prior to the melt being poured into the mold. Insome embodiments, the amount of reactive component in the melt can bebetter controlled by using a partial pressure of the reactive componentin the vacuum chamber surrounding the melt. The partial pressure of thereactive component can have a chemical activity approximately equal tothe chemical activity of the reactive component in the melt. The partialpressure of the reactive component can either be used to replace thepartial pressure of argon or be added to the partial pressure of argon.The latter would provide a higher total pressure surrounding the meltand would further reduce loss by evaporation.

An example of this procedure is the melting of the main alloy componentsof Iron, Manganese, Niobium and carbon under vacuum followed by theaddition of argon at a partial pressure of 200 torr. At the appropriatetime in the melt process, the partial pressure in the chamber isincreased with the addition of chlorine gas of approximately 1 torr andthe reactive chloride salts are released into the melt from the additionchamber. The melt is allowed to mix and poured into the mold forcooling.

Although the invention has been described with reference to thepresently preferred embodiments, it should be understood that variouschanges and modifications, as would be obvious to one skilled in theart, can be made without departing from the spirit of the invention.Accordingly, the invention is limited only by the following claims.

What is claimed:
 1. A method of producing a biodegradable alloy that isaustenitic in structure and includes iron, at least one additionalmetallic element, and an iron reactive component, wherein the ironreactive component is dispersed within the biodegradable alloy at aconcentration between about 0.1 ppm to about 500 ppm, and wherein thedegradation rate of the biodegradable alloy, when implanted in abiological subject, is greater than the degradation rate of an alloyhaving the same composition as the biodegradable alloy except theabsence of the iron reactive component, the method comprising: meltingiron, the at least one additional metallic element, and a saltcontaining the iron reactive component to produce a mixture; andcontacting the mixture with a gas containing the iron reactive componentto produce the biodegradable alloy.
 2. The method of claim 1, whereinthe salt containing the iron reactive component is selected from thegroup consisting of sodium fluoride, sodium chloride, copper chloride,copper fluoride, magnesium chloride, silver chloride, calcium chloride,calcium fluoride, iron chloride, and a combination thereof.
 3. Themethod of claim 1, wherein the gas containing the iron reactivecomponent has a partial pressure of at least about 0.1 torr, at leastabout 0.2 torr, at least about 0.5 torr, at least about 0.8 torr, atleast about 1 torr, at least about 2 torr, at least about 5 torr, atleast about 10 torr, at least about 50 torr, or at least about 100 torr.4. The method of claim 1, the iron reactive component is a halogencomponent.
 5. The method of claim 4, wherein the halogen component isselected from the group consisting of chloride, fluoride, bromide, andiodide.
 6. The method of claim 5, wherein the halogen component ischloride or fluoride.
 7. The method of claim 5, wherein the gascontaining the iron reactive component is selected from the groupconsisting of chlorine, fluorine, bromine, and iodine.
 8. The method ofclaim 1, further comprising mixing the iron reactive component withargon gas to produce the gas containing the iron reactive component. 9.The method of claim 8, wherein the argon gas has a partial pressure ofat least about 10 torr, at least about 20 torr, at least about 50 torr,at least about 80 torr, at least about 100 torr, at least about 150torr, at least about 200 torr, at least about 250 torr, at least about300 torr, or at least about 500 torr.
 10. The method of claim 1, whereinthe biodegradable alloy includes an austenite-promoting component and acorrosion-resisting component.
 11. The method of claim 1, wherein thebiodegradable alloy contains between about 20% to 40% manganese byweight.
 12. The method of claim 1, wherein the biodegradable alloycontains less than about 0.3% niobium by weight.
 13. The method of claim1, wherein the biodegradable alloy contains less than about 1% carbon byweight.
 14. The method of claim 1, wherein the biodegradable alloyincludes manganese and niobium.
 15. The method of claim 1, wherein thebiodegradable alloy includes at least about 0.01% to about 0.1% anon-metallic element by weight.
 16. The method of claim 15, wherein thebiodegradable alloy includes at least about 0.01% to about 0.1% carbonby weight.
 17. The method of claim 1, wherein the biodegradable alloy isin a form of an implantable medical device.
 18. The method of claim 17,wherein the implantable medical device is a bone screw, a bone anchor, atissue staple, a craniomaxillofacial reconstruction plate, a fastener, areconstructive dental implant, or a stent.
 19. The method of claim 17,further comprising coating the implantable medical device with atherapeutic agent.
 20. The method of claim 17, further comprisingcoating the implantable medical device with a biodegradable hydrogel.21. The method of claim 17, wherein the implantable medical device has ageometry that maximizes the surface to mass ratio.
 22. The method ofclaim 17, wherein the implantable medical device includes a hollowopening or passageway formed therein.
 23. The method of claim 1, whereinthe concentration of the iron reactive component in the biodegradablealloy is between about 1 ppm to about 500 ppm, between about 10 ppm toabout 300 ppm, or between about 50 ppm to about 150 ppm.
 24. The methodof claim 1, wherein the concentration of the iron reactive component inthe biodegradable alloy is about 200 ppm.
 25. The method of claim 1,wherein the iron, the at least one additional metallic element, and thesalt containing the iron reactive component are melted in the presenceof the gas containing the iron reactive component.
 26. A biodegradablealloy produced by the method of claim 1.